Drug treatment for brain metastases

Musa Mayer: What about trying other approaches that may have a potential, like drugs, when the maximum dose of radiation has been received?

Andrew Seidman: This is something that Iâ€™m particularly interested in. We think of most chemotherapy drugs as being relatively ineffective against brain metastases. I think the (scientific) literature would support that contention in general, but with some exceptions. There are agents that do have the potential of penetrating across the blood-brain barrier, and we know that the blood-brain barrier may be impaired in patients who have brain metastases.

One of the more recent agents that has been a focus of attention for its effectiveness against brain metastases is capecitabine (Xeloda), an oral fluoropyrimidine which is converted first by the liver, then intracellularly by the cancer cells into 5-FU, or fluorouricil. It has been reported in Phase II trials to actually cause responses in 20 to 25 percent of patients who have measurable brain metastases. The M.D. Anderson group did report on the combination of Xeloda and Temodar (temozolomide), although itâ€™s not clear how much Temodar contributes, since Xeloda alone has also been reported to cause regression in brain metastases. Temodar as a single agent hasnâ€™t seemed to be particularly effective against breast cancer brain metastases. The only way to know what the contribution of Temodar is would be to do a randomized trial of Xeloda, with or without Temodar.

Even drugs that have been visibly publicized lately for their potential exciting role in treating brain metastases, such as lapatinib (Tykerb), the HER1, HER2 dual tyrosine kinase inhibitorâ€”the effectiveness, to me, has been rather disappointing. In the trial in patients with HER2-positive brain metastases that have progressed despite radiation, only 15 out of 241, or 6% of patients, actually had a measurable response. So for me, the glass is half empty, rather than half full.

Currently, we at Memorial, in collaboration with Dr. Peereboom at the Cleveland Clinic, are examining the potential role of a newer epothilone drug, called patupilone, which is a cousin of ixabepilone (Ixempra) which was just approved for the treatment of metastatic breast cancer last month. Patupilone has characteristics that would lead one to believe it could penetrate across the blood-brain barrier, so we just this year initiated a trial to see its potential role in treating patients with progressive brain metastases who have already had whole brain radiation.

MM: Are there other drugs under development for the treatment of brain metastases?

AS: Iâ€™m not aware of any other drugs that are specifically in trials to examine their role in brain metastases. In the past weâ€™ve often excluded patients with brain metastases, when weâ€™ve been looking at drugs with the potential to cause remissions in extracranial sites of disease such as liver, lung and bone. I think we should revisit the wisdom of that, because the notion there was that you wouldnâ€™t want to have a patient whose life expectancy or performance status (a measure of functioning) would be poor enough that it would stack the deck against your finding the effectiveness of a drug in non-brain sites. So often patients with brain mets have been excluded, and that has limited our ability to get a signal from a wide variety of drugs as to whether there is potential effectiveness in the brain.

MM: Do you see a change in the willingness of companies developing drugs to enroll patients with brain mets?

AS: Yes, I do see a change. To be fair, I think that some of the criteria that are applied arenâ€™t meant to discriminate. Most often, eligibility criteria for trials are meant to keep the study scientifically rigorous, and to protect patients from being exposed to unnecessary harm. Having said that, I think that companies that have agents that have properties, in terms of molecular weight, and that have the chemical properties that would lead one to believe they might cross the blood-brain barrier, I think thereâ€™s a willingness to rethink that exclusion criteria.

MM: What about Avastin (bevacizumab) and other anti-angiogenic drugs?

AS: The initial concerns have been that this is a drug that has been shown to precipitate vascular events such as bleeding, as well as venous and arterial blood clotting. Therefore, in the setting of brain metastasis, in the intracranial compartment, there would be a potential risk for intracranial hemorrhage (stroke). I honestly donâ€™t think we have enough data to know if this is a valid concern. The same concerns would be true of other anti-angiogenic agents, but fortunately weâ€™ll begin to see in larger Phase III trials of drugs like sunitinib (Sutent) and sorafenib whether these concerns are really well founded or not.

MM: Will we be able to draw on the safety data of patients with other cancers that metastasize to the brain?

Well, yes and no. Not all brain metastases are equally vascular and likely to bleed. For example, the cancers that are most likely to metastasize to the brain generally are related to the frequency of the disease, such as breast and lung. Also, the biological propensity for them to travel to the brain, and that would include diseases like melanoma and renal cell carcinoma. There have been some reports of excessive hemorrhaging into the brain in patients with renal cell carcinoma treated with anti-angiogenic therapy. So I think the chapter hasnâ€™t been fully written to inform us about the safety of various anti-angiogenic agents in the management of patients who have brain metastases.

MM: What havenâ€™t we covered that you would like to communicate to people who are facing a diagnosis, or who are at high risk, living in fear of brain metastases?

I think that women who have HER2-positive metastatic breast cancer should not feel timid about asking their oncologists, even in the absence of worrisome neurological symptoms, about the potential of doing periodic brain imaging. While the issue is controversial, not knowing can cause psychological stress, and screening can allow earlier intervention, and the possible avoidance of neurological dysfunction down the road. While we lack prospective evidence to show that benefit, I think this is not an unreasonable tack to take when a condition is likely to occur in about one-third of all such patients, that is, the incidence of brain metastases in patients with HER2-positive metastatic disease.

On the other side of the coin, I would just reiterate one of the things I said at the very outset, and that is that patients who might be visiting this website and reading this discussion who have early stage breast cancer, that fortunately the incidence of brain metastases in patients who have early stage diseaseâ€”certainly Stage I or IIâ€”is sufficiently small that screening of the brain in these patients is probably not indicated. Certainly, I understand the need to be thorough, but itâ€™s not a standard of care to do brain imaging in women with a new diagnosis of breast cancer.

I think itâ€™s important for patients and their families to understand that the brain is a very complex organ. Not all brain metastases are alike, and depending upon the number, the volume, the size and the position of brain metastases, some patients may be very highly functional and not symptomatic, while other patients may be significantly symptomatic and impaired in terms of their ability to perform the activities of daily living. Attention to depression in this setting is important. The need for rehabilitation and physical therapy depending upon neurological deficits is also important

MM: Youâ€™ve covered a tremendous spectrum of information. Thank you so much.